Gastrointestinal electrical stimulation for the treatment of pacreatitis

ABSTRACT

A method of preventing acute pancreatitis comprising positioning stimulatory electrodes in the stomach of an individual in need thereof; and administering repetitive trains of short pulse gastrointestinal electrical stimulation effective for suppressing the inflammatory response in the pancreas is provided herein. The electrodes are placed by laproscopic, endoscopic or surgical means. The gastrointestinal stimulation activates vagal reflexes. The activation of the vagal reflexes is via the gastric and pancreatic afferents. The gastrointestinal stimulation also activates the axonal reflexes. The activation of the axonal reflexes is via the dichotomous branches of the spinal nerves. The electrical stimulation is administered concurrently with an endoscopic procedure or immediately following an endoscopic procedure. Also, provided herein is a method of preventing inflammation of a visceral organ comprising positioning a stimulatory electrode in proximity of descending efferents in the vagus, innervating the visceral organ, of an individual in need thereof, and administering repetitive trains of short pulse electrical stimulation effective in activating nicotinic receptors.

RELATED APPLICATION

This application claims priority to U.S. provisional application No.61/021,473, filed Jan. 16, 2008. This application also claims priorityto PCT/US2009/031317, filed Jan. 16, 2009.

FEDERAL GRANT INFORMATION

The present disclosure was supported by a grant DK-063733-01, from theNational Institute of Health. The U.S. Government may have some rightsto the disclosure.

BACKGROUND

Acute pancreatitis is a sudden inflammation that occurs over a shortperiod of time. In the majority of cases, acute pancreatitis is causedby gallstones or heavy alcohol use. Other causes include medications,infections, trauma, metabolic disorders, and surgery. In about 10% to15% of people with acute pancreatitis, the cause is unknown. Endoscopicretrograde cholangiopancreatography (ERCP) has been used for thediagnosis and treatment of pancreatic diseases. This procedure isperformed on an outpatient basis under sedation (rarely under generalanesthesia). ERCP is associated with a 5%-10% risk of pancreatitis. Therisk is increased in those cases where cannulation of the ducts isdifficult, the pancreas is normal, or when a sphincterotomy is performedin the setting of sphincter of Oddi dysfunction. A prior history ofERCP-induced pancreatitis is also a risk factor. Other less common risksinclude bleeding, infection and perforation. Particularly in the settingof pancreatic disease, it is a specialized procedure that should beperformed only by experienced endoscopists.

There is a high morbidity and mortality rate for pancreatitis. SeeBaron, et al, 1999 and Steer et al., 1995. Pharmacologic means ofdecreasing pancreatic secretion have been attempted with limited successbecause of the dose-limiting side effects encountered with the drugs,their lack of specificity or their lack of availability. The vagusnerves are strongly implicated in the pathophysiology of pancreatitis.Yoshinaga, et al., 2000. Atropine is a drug that blocks parasympathetic(vagal) nerve endings. It is known to be desirable to use atropine inacute pancreatitis patients to down-regulate pancreatic activity.Unfortunately, for most such patients, this drug cannot be used due toits many side effects.

A need continues to exist for additional feasible and suitable means totreat pancreatitis. Likewise, a need continues to exist for additionalfeasible and suitable means to treat other gastrointestinal tractdisorders.

SUMMARY

Provided herein is a method of preventing acute pancreatitis comprisingpositioning stimulatory electrodes in the stomach of an individual inneed thereof; and administering repetitive trains of short pulsegastrointestinal electrical stimulation effective for suppressing theinflammatory response in the pancreas.

Also, provided herein is a method of preventing acute pancreatitiscomprising positioning a stimulatory electrode in the stomach, inproximity of a dichotomously branched spinal nerve innervating thestomach and the pancreas, of an individual in need thereof, andadministering repetitive trains of short pulse electrical stimulationeffective, at least in part in, blocking the pro-inflammatory spinalreflexes.

Further, provided is a method of preventing inflammation of a visceralorgan comprising positioning a stimulatory electrode in proximity ofdescending efferents in the vagus, innervating the visceral organ, of anindividual in need thereof, and administering repetitive trains of shortpulse electrical stimulation effective in activating nicotinicreceptors.

More specifically, the disclosure provides a method of preventing acutepancreatitis in a subject comprising: positioning stimulatory electrodesin the peritoneal cavity of the subject and administering repetitivetrains of short pulse gastric electrical stimulation effective forsuppressing the inflammatory response in the pancreas.

In certain aspects, the method may be used when acute pancreatitisdevelops due to an endoscopic procedure. Optionally, the endoscopicprocedure selected from the group consisting of Endoscopic retrogradecholangiopancreatography (ERCP), and endoscopic sphincterotomy.

In certain aspects of the disclosure the method of administeringrepetitive trains of short pulse gastric electrical stimulation mayinclude trains of pulses are set on for a range of period between about0.1 seconds to less than or equal to 5 seconds and set off for a rangeof period between about 0 to less than or equal to 10 minutes.Optionally the methods include repetitive trains of pulses administeredin the range between about IHz. to less than or equal to 150 Hz.Optionally, the methods may include repetitive trains of pulses have apulse width in the range between about 0.1 ms to less than or equal to2.0 ms. Optionally the methods may include repetitive trains of pulseshave an amplitude in the range between about 0.1 mA to less than orequal to 20.0 mA.

In certain aspects of the disclosure the methods described above mayfurther include placing the electrodes by laproscopic, endoscopic orsurgical means.

In certain aspects of the disclosure, in methods involvinggastrointestinal stimulation, such stimulation may activate vagalreflexes. Optionally, activation of the vagal reflexes is via thegastric and pancreatic afferents. Optionally in methods involvinggastrointestinal stimulation, the stimulation activates the axonalreflexes. Optionally, activation of the axonal reflexes is via thedichotomous branches of the spinal nerves innervating the stomach andthe pancreas.

In certain aspects of the disclosure pertaining to the methods describedabove, electrical stimulation is administered concurrently with anendoscopic procedure. Optionally or alternatively, in certain aspects ofthe disclosure pertaining to the methods described above, electricalstimulation is administered following an endoscopic procedure.

Certain aspects of the disclosure pertain to a method of preventingacute pancreatitis in a subject comprising: positioning a stimulatoryelectrode in the peritoneal cavity, in proximity of a dichotomouslybranched spinal nerve innervating the stomach and the pancreas, of anindividual in need thereof, and administering repetitive trains of shortpulse electrical stimulation effective, at least in part in, blockingthe pro-inflammatory spinal reflexes.

Optionally, in the method described above repetitive trains of pulsesare set on for a range of period between about 0.1 seconds to less thanor equal to 5 seconds and set off for a range of period between about 0to less than or equal to 10 minutes. Optionally, the repetitive trainsof pulses are administered in the range between about IHz. to less thanor equal to 150 Hz. Optionally, the repetitive trains of pulses have apulse width in the range between about 0.1 ms to less than or equal to2.0 ms. Optionally, the repetitive trains of pulses have an amplitude inthe range between about 0.1 mA to less than or equal to 20.0 mA.

In certain aspects of the method described above electrodes are placedby laproscopic, endoscopic or surgical means. Optionally the electrodesare stimulatory electrodes and are placed in the stomach, smallintestines, colon or anorectum.

Certain aspects of the disclosure pertain to a method of preventinginflammation of a visceral organ comprising positioning a stimulatoryelectrode in proximity of descending efferents in the vagus, innervatingthe visceral organ and administering repetitive trains of short pulseelectrical stimulation effective in activating nicotinic receptors.

Certain aspects of the disclosure pertain to a method of preventingacute pancreatitis in a subject comprising: positioning stimulatoryelectrodes in the peritoneal cavity of the subject and administeringrepetitive trains of short pulse gastric electrical stimulationeffective for suppressing the inflammatory response in the pancreas.

Certain aspects of the disclosure pertain to a method of preventingacute pancreatitis in a subject comprising: positioning a stimulatoryelectrode in the peritoneal cavity, in proximity of a dichotomouslybranched spinal nerve innervating the stomach and the pancreas, of anindividual in need thereof, and administering repetitive trains of shortpulse electrical stimulation effective, at least in part in, blockingthe pro-inflammatory spinal reflexes.

Certain aspects of the disclosure pertain to a method of preventinginflammation of a visceral organ comprising positioning a stimulatoryelectrode in proximity of descending efferents in the vagus, innervatingthe visceral organ and administering repetitive trains of short pulseelectrical stimulation effective in activating nicotinic receptors.

The details of one or more embodiments of the disclosure are set forthin the accompanying drawings and the description below. Other features,objects, and advantages of the disclosure will be apparent from thedescription and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In order that the manner in which the above recited and otherenhancements and objects of the disclosure are obtained, a moreparticular description of the disclosure briefly described above will berendered by reference to specific embodiments thereof, which areillustrated, in the appended drawings. Understanding that these drawingsdepict only typical embodiments of the disclosure and are therefore notto be considered limiting of its scope, the disclosure will be describedwith additional specificity and detail through the use of theaccompanying drawings in which:

FIGS. 1A-1B illustrate two pathways by which electrical stimulation ofthe peritoneal cavity can modulate inflammation in the pancreas: thevagal reflex carried by gastric vagal afferents and pancreatic vagalefferents (FIG. 1A) and/or axonal reflex within a dichotomous singlenerve innervating both the stomach and the pancreas (FIG. 1B).

FIG. 2A shows the percentage of pancreatic (red) and gastric (green) DRGneurons that are double labeled at various spinal segments. FIG. 2B is arepresentative photomicrograph of several double labeled neurons in aDRG section.

FIG. 3 illustrates an example of an TRPV1 staining in gastropancreaticneuron.

FIG. 4 shows that intragastric capsaicin causes pancreatic edema.

FIG. 5 shows net water content in the pancreas (edema) 24 h aftercerulean injections with and without GES.

FIG. 6 A-F shows various electrode leads with radially spaced arms invarious configurations inserted into and through the hollow bore of aneedle.

FIG. 7 A, B shows electrode leads with radially spaced arms insertedthrough the skin, panniculus and gastrointestinal wall after removal ofinsertion needles. FIG. 7C shows bridged insertion needles.

FIG. 8A-D shows methods and devices for using a needle with a guide rodfor electrode leads with radially spaced arms.

FIG. 9A shows a method of placing gastrointestinal leads with apercutaneous endoscopic gastronomy type device. FIG. 9B shows conductivewire through an electrode lead with an insertion axis and a plurality ofradially spaced arms.

LIST OF REFERENCE NUMERALS

1 electrode lead with an insertion axis

2 needle

3 hollow bore

4 entrance tip

5 first or a single pair of radially spaced arms

6 second or additional pair of radially spaced arms

7 bridge

8 skin

9 panniculus

10 gastrointestinal wall

11 guide rod

12 skin bolster

13 gastric bolster

14 plurality of electric leads

15 lead ends

16 conductive wire

17 second needle

DETAILED DESCRIPTION OF THE DISCLOSURE

The particulars shown herein are by way of example and for purposes ofillustrative discussion of the preferred embodiments of the presentdisclosure only and are presented in the cause of providing what isbelieved to be the most useful and readily understood description of theprinciples and conceptual aspects of various embodiments of thedisclosure. In this regard, no attempt is made to show structuraldetails of the disclosure in more detail than is necessary for thefundamental understanding of the disclosure, the description taken withthe drawings and/or examples making apparent to those skilled in the arthow the several forms of the disclosure may be embodied in practice.

The following definitions and explanations are meant and intended to becontrolling in any future construction unless clearly and unambiguouslymodified in the following examples or when application of the meaningrenders any construction meaningless or essentially meaningless. Incases where the construction of the term would render it meaningless oressentially meaningless, the definition should be taken from Webster'sDictionary, 3rd Edition.

As used herein, all percentages are percentages by weight, unless statedotherwise.

As used herein, the “gastrointestinal tract” (GI tract) in certaininstances may refer to the “gut” or the “alimentary canal” that is acontinuous, coiled, hollow, muscular tube that winds through the ventralbody cavity. It is open to the external environment at both ends. In ahuman, its organs (gastrointestinal organs) generally include the mouth,pharynx, esophagus, stomach, small intestine (duodenum, jejunum, andileum), and large intestine (cecum, appendix, colon, rectum, and analcanal). The large intestine leads to the terminal opening, or anus.

The “gastrointestinal wall” in certain instances may refer to thecontinuous, coiled, hollow, muscular tube that is the gastrointestinaltract. The wall generally defines the center (lumen) of the GI tract(the hollow portion of the tube). The wall has a thickness defining aninterior wall adjacent to the center of the GI tract and an exteriorwall.

As used herein, “gastrointestinal action” in certain instances may referto any GI actions. Thus, gastrointestinal action includes, for example,gastrointestinal electrical activity, gastrointestinal contractileactivity (such as stomach contractile activity), gastrointestinalmotility, gastric emptying, gastrointestinal pressure, gastrointestinalimpedance, and afferent nerve activity (including vagal nerve,sympathetic nerves, and spinal nerves).

A subject in certain instances may refer to an animal, including ahuman, subject. For non-human animal subjects, the particular structureof the GI tract may differ from that of a human. For such non-humananimal subjects, the gastrointestinal tract, as used herein, refers tothat non-human animal's known GI tract and GI organs. It is understoodthat the first step of the present disclosure includes selecting asubject which would benefit from the method of the subject, such as, forexample, selecting a subject who is suffering from gastrointestinalpain.

An “optimum level” in certain instances may refer to a pre-determinedtarget, which is determined based on the desired outcome. For example,in GES (see below), the definition of optimization is based on anoptimal combination of efficacy, safety and feasibility. That is, theoptimal GES settings are those that result in a significant reduction inpain (efficacy) but do not induce undesired symptoms, such as nausea orvomiting (safety) with minimal energy (maximally feasible for animplantable device). Iterative adjustments of stimulation parameters aremade to achieve this result. For any particular gastrointestinal action,an “optimum level” or desirable level can be determined by monitoringthe appropriate GI action. As another example, an appropriate amount ofGI pressure at the esophageal sphincter can be determined which preventsreflex of stomach juices into the esophagus, while still allowing thepassage of food items into the stomach. With this predetermined “optimumlevel”, a stimulatory electrode can be established with a sensor tomaintain this optimum level. The optimum level is thus fact and subjectspecific, but readily determinable with routine experimentation, takinginto account the goal of an optimal combination of efficacy, safety andfeasibility.

A “stimulatory electrode” in certain instances may refer to a conductorof electricity through which current enters a medium (a subject),whereas a “sensor” refers to a conductor of electricity through whichcurrent leaves a medium (a subject). Typically, for gastrointestinaluses, the stimulatory electrodes and sensors are constructed ofteflon-insulated wires such as are used for cardiac pacing wires. Thestimulatory electrode is electrically connected (i.e., conductivelyconnected) to a source of electrical current (often referred to as apacemaker where a set pattern of electrical current is delivered), andthe sensor is electrically connected to a device for determining thelevel of electrical current “sensed” by the sensor (an electricalrecorder, for example). The stimulatory electrode is thus used to“generate” electrical current and the sensor is thus used to “detect”electrical current. Note that the stimulatory electrode can be used to“generate” electrical current, which is itself a defined“gastrointestinal action”, but the generation of electrical current canalso produce other gastrointestinal actions (such as, for example,stomach contraction or esophageal pressure). The language “generating”GI action is thus intended to cover both concepts, i.e. the generationof the initial electrical current and the ultimate gastrointestinalaction which is “generated” as a result of the current (i.e. thecontraction or pressure).

“Operatively connected” in certain instances may refer to the connectionbetween the stimulatory electrode and the sensor, and indicates that theoperation of one is connected to the operation of the other. Inparticular, the sensor connects to a device which determines the levelof electrical current sensed by the sensor. A representation of thatlevel is then fed to the source of electrical current that iselectrically connected to the stimulatory electrode. The source ofelectrical current is provided with a programmable computer circuit thatenables the level from the sensor to determine, or dictate, theoperation of the source (i.e., electrical current is generated by thesource and fed through the stimulatory electrode in response to and anin relation to the amount of the level of electrical activity sensed bythe sensor). Thus, the “operatively connected” stimulatory electrode andsensor enable the retrograde feedback concept to occur.

“Positioning” a stimulatory electrode or a sensor in certain instancesmay refer to placement of the stimulatory electrode or sensor on or in asubject. Placement or positioning of stimulatory electrodes can beaccomplished by laproscopic, endoscopic or surgical means. In general,laparoscopic placement of electrodes is performed by inserting a scopethrough one trocar or sheath and the electrode through one or more othertrocars or sheaths. The trocars are sleeves which are inserted through abody opening which may be a surgically made opening or portal throughthe skin, muscle and peritoneal membrane. The trocar typically has aninside diameter of 10 millimeters. Often the body cavity, such as theabdominal peritoneal area is inflated with low pressure carbon dioxide.An insufflation pressure of about 12 millimeters of HG or less ismaintained during the operation by a sealing membrane located in thetrocar opening comprising a thin rubber material having a small diameterhole of approximately 3 millimeters therein. The electrodes are insertedthrough the membrane hole which stretches to accommodate the larger sizethereby forming and effective seal

Endoscopic placement of the electrodes can be accomplished by eitherusing the endoscope for both visualization as well as insertion ofelectrodes or by endoscopic visualization to guide insertion of theelectrodes. For the latter method, the conscious patient is sedated andan endoscope is inserted into the stomach via the mouth. Then, a sharp,long and small needle with a hole in the middle (similar to needles usedfor the placement of percutaneous endoscopic gastronomy tubes) isinserted into the stomach by puncturing the skin. A teflon-insulatedwire, peeled off at the distal portion, is then extended, underendoscopic observation, into the stomach via the hole of the needle. Theexposed, peeled off portion of the inserted teflon-insulated wire servesas an electrode. The needle is removed after the insertion of the wire.The wire has an engaging means. The engaging means allow for engagementof the wire with the mucosa, when the wire is slowly pulled from theexterior, and stops it from being further pulled out. On the externalend the wire is attached to the abdominal skin and protected frominfection.

The engaging means for the electrode refers to any suitable means thatwould allow for the successful engagement of the electrodes to themucosa. These include but are not limited to barbs, expandable hooks,and suction based fasteners arranged at the distal tip of theelectrodes.

“Periodically” in certain instances may refer to evenly or unevenlyspaced time intervals.

“Differs from” in certain instances may refer to a statisticallysignificant variation between two compared values, and therefore doesnot always require a difference in orders of magnitude. It should beapparent that where small values are compared, statistically significantvariations can likewise be very small, and where large values arecompared, statistically significant variations can be large. Conversely,“substantially equals” refers to a statistically insignificant variationbetween two compared values.

“Electrical field stimulation” in certain instances may refer to thegeneration of an “electrical field”, which indicates that the area ofdistribution of the electrical current from the stimulation encompassesthe entire area between and/or surrounding two or more stimulatoryelectrodes, and “field” is used to imply that the two or morestimulatory electrodes are positioned at least about three centimetersapart (thus the term “field” to differ from prior stimulations where thetwo electrodes of a pair are positioned in close proximity to oneanother and do not generate a “field”).

A “device” in certain instances may refer to any suitable item which canreadily be and is desirable to be placed in the GI tract. Such devicescan include, for example, stimulatory electrodes and sensors for use inthe GES method of the subject disclosure. Such devices could alsoinclude a small balloon to be used to provide pressure within theesophagus or small/large intestine. A small gauge for measurement ofpressure could be a device in accordance with the subject disclosure.

Electrical stimulation refers to an electrical signal, which includes atrain of pulses. A train of pulses refers to a method in which thestimulus is composed of repetitive trains of short pulses derived from acombination of two signals, a) a continuous short pulse with highfrequency (in the order of 5 to 150 Hz), and b) control signal to turnthe pulses on or off, such as “X” seconds on and “Y” seconds off. Theaddition of “X” and “Y” then determines the frequency of the pulsetrain. A frequency approximately equal to the physiologic frequency ofstimulation will be performed using trains of pulses. The train will beset on for a period of 0.1 s to 5 seconds and set off for a period of 0to 10 min. The pulses within a train have a frequency of 5 to 150 Hzwidth of 0.1 to 2 ms and amplitude of 0.1 mA to 1 OmA or thecorresponding voltages that will produce the described current. Themethods of providing electrical field stimulation to a gastrointestinalorgan are disclosed in WO2001/076690 which is hereby incorporated byreference herein. A discussion of trains of short pulse electricalstimulation is provided in Zhang et al., 2006, which is herebyincorporated by reference herein. Electrical stimulation is also capablefrom a magnet.

“Long pulse” electrical stimulation in certain instances may refer to anelectrical signal which has a long width, such as in the order of fromabout 1 to about 900 milliseconds, or about 2 to about 600 milliseconds,and has a frequency approximately equal to the physiologic frequency ofthe gastric slow wave of the subject. For example, the long pulseelectrical stimulation has a frequency of about ±20%, or about ±10%, ofthe physiologic frequency of the gastric slow wave of the subject.

“Short pulse” electrical stimulation in certain instances may refer toan electrical signal which has a short width, such as in an order offrom about 50 to about 999 microseconds, or about 100 to about 300microseconds and having a frequency from about 5 Hz to about 500 Hz. Thenumber of short pulses applied range from 1 to about 50.

Synchronization or synchronized in certain instances may refer toapplying the long pulse and/or short pulse electrical stimulationsubstantially concurrently with the occurrence of the gastric slow waveof the subject.

Electrical stimulation of the gastrointestinal tract has been proposedto treat motility related disorders and other gastrointestinal diseases.The electrical stimulation has been proposed in a number of forms, suchas, e.g., pacing, electrical contractile stimulation or otherstimulation, e.g., to treat nausea or obesity. Electrical pacing of thegastrointestinal tract is generally defined as a periodic electricalstimulation that captures and/or controls the frequency of thepacesetter potential or slow wave activity of the intestinal organ(including in a retrograde direction). Electrical contractilestimulation generally refers to stimulation that directly causes orresults in muscular contraction associated with the gastrointestinaltract. There have been a number of reports on Gastric electricalstimulation for the treatment of gastrointestinal motility disorders inboth dogs and humans (U.S. Pat. Nos. 5,423,872, 5,690,691, and5,836,994; PCT International Publication No. WO 99/30776; Bellahsene etal. 1992; Mintchev et al. 1998; Mintchev et al. 1999; Mintchev et al.2000; Chen et al. 1998; Chen et al. 1995). These disorders arecharacterized by poor contractility and delayed emptying and the aim ofelectrical stimulation in this setting is to normalize the underlyingelectrical rhythm and improve these parameters. Gastric emptying playsan important role in regulating food intake. Several studies have shownthat gastric distention acts as a satiety signal to inhibit food intake(Phillips and Powley 1996) and rapid gastric emptying is closely relatedto overeating and obesity (Duggan and Booth 1986). Obese subjects have amore rapid emptying rate than non-obese subjects (Wright et al. 1983).In general, this is done by antegrade or forward gastric (or intestinal)stimulation. Previous work on antegrade gastrointestinal stimulation hasbeen focused on its effects on gastric myoelectrical activity, gastricmotility, and gastric emptying, (Lin et al. 1998; Eagon and Kelly 1993;Hocking et al. 1992; Lin et al. 2000; McCallum et al. 1998; Miedema etal. 1992; Qian et al. 1999; Abo et al. 2000; Bellahsene et al. 1992).Gastrointestinal electrical stimulation, as used in the presentdisclosure, alters sympathetic nerves, such as the spinal afferentneurons.

Pancreatitis is a severe disease that is associated with high morbidityand mortality. It is typically caused by alcohol abuse or gallstones andmost patients suffering from pancreatitis require hospitalization. Acutepancreatitis is a major and potentially serious complication ofEndoscopic retrograde cholangiopancreatography (ERCP) and endoscopicsphincterotomy, occurring at a frequency ranging from 1-10%. Although,the exact pathogenesis of ERCP induced pancreatitis is unknown it mayinvolve activation of pancreatic enzymes, vascular impairment,activation of clotting, kinin and arachidonic acid pathways andrecruitment of inflammatory cells. These events lead to aself-sustaining casade of parenchymal cell injury of pancreas. Notherapies are available to treat the illness; only palliative care isavailable.

Current research has implicated the inflammatory response as playing acritical role in the development of pancreatitis. Inflammation resultsfrom the up-regulation of a multitude of pro-inflammatory signalingmolecules including TNF-α, IL-6, IL-8 and others. Activation of theinflammatory pathway in the pancreas is thought to damage pancreatictissue, thereby leading to the disease. Inflammation in any tissuerequires communication across many systems including immune, endocrineand nervous systems. Information from the pancreas, like other visceralorgans, is conveyed to the central nervous system principally via twopathways—the spinal afferents that generally convey painful stimuli andthe vagus afferents that carry non-painful and physiological stimuli.Cytokines and other inflammatory factors can activate these pathways andinitiate multiple responses including fever and other acute phasereflexes. In addition an anti-inflammatory reflex, the nicotinicanti-inflammatory pathway,” is initiated that involves descendingefferents in the vagus and dampens the macrophage response by activationof specific nicotinic receptors on these cells.

Traditionally, this pathway is considered a classical vagal reflex,although alternatively, an axon reflex utilizing cholinergic vagalafferents might be implicated.

The vagus nerve plays an important role in the parasympatheticantiinflammatory pathway. The nervous system, through the vagus nerve,controls inflammation by decreasing the release of TNF-α from endotoxinstimulated macrophages. This anti-inflammatory effect is mediated by aninteraction of acetylcholine, the principal vagal neurotransmitter, withmacrophage cholinergic nicotinic receptors expressing the α7 subunit. Infact, a specific blocker of parasympathetic (vagus nerves) control ofsecretion demonstrated a shortened recovery period in patients withacute pancreatitis. See Zapater, et al., 2000; Norton, et al., 2001.However, most of these drugs cannot be used routinely due to many sideeffects.

By contrast to vagal afferents, spinal afferents are generally thoughtto actually promote inflammation via local releases of substances suchas SP and CGRP. A single spinal nerve is capable of innervating both thestomach and the pancreas by diverging at its terminal into separatefibers. Thus, the dichotomous spinal innervation of the stomach and thepancreas, enables electrical stimulation of the stomach to mediateinhibition of the proinflammatory reflexes that serves to causeinflammation of the pancreas. Hence, electrical stimulation of thestomach could modulate inflammation of the pancreas via two potentialpathways: 1) activation of anti-inflammatory vagal reflexes involvinggastric afferents and pancreatic efferents and/or 2) suppression ofpro-inflammatory axonal reflexes involving the dichotomous branches ofthe spinal nerves and/or 3) activation of other anti-inflammatory neuralpathways between the stomach and pancreas.

Thus, disclosed herein is a method of preventing acute pancreatitis in asubject comprising positioning stimulatory electrodes in the peritonealcavity of the subject and administering repetitive trains of short pulsegastrointestinal electrical stimulation effective for suppressing theinflammatory response in the pancreas. Specifically, in variousembodiments, the acute pancreatitis develops due to an endoscopicprocedure. In general, in various embodiments, the endoscopic procedureis selected from the group consisting of Endoscopic retrogradecholangiopancreatography (ERCP), and endoscopic sphincterotomy.Moreover, the repetitive trains of pulses are set on for a range ofperiod between about 0.1 seconds to less than or equal to 5 seconds andset off for a range of period between about 0 to less than or equal to10 minutes. Further, the repetitive trains of pulses are administered inthe range between about IHz. to less than or equal to 150 Hz, a pulsewidth in the range between about 0.1 ms to less than or equal to 2.0 ms,and an amplitude in the range between about 0.1 mA to less than or equalto 20.0 mA. Additionally, the electrodes are placed by laproscopic,endoscopic or surgical means. Specifically, the gastrointestinalstimulation activates vagal reflexes. Moreover, the activation of thevagal reflexes is via the gastric and pancreatic afferents.Additionally, the gastrointestinal stimulation activates the axonalreflexes. Further, the activation of the axonal reflexes is via thedichotomous branches of the spinal nerves innervating the stomach andthe pancreas. In general, the electrical stimulation is administeredconcurrently with an endoscopic procedure. Additionally, the electricalstimulation is administered following an endoscopic procedure.

Further, disclosed is a method of preventing acute pancreatitis in asubject comprising positioning a stimulatory electrode in the peritonealcavity, in proximity of a dichotomously branched spinal nerveinnervating the stomach and the pancreas, of an individual in needthereof, and administering repetitive trains of short pulse electricalstimulation effective, at least in part in, blocking thepro-inflammatory spinal reflexes. Specifically, the acute pancreatitisis due to an endoscopic procedure. In general, the electricalstimulation is administered concurrently with an endoscopic procedure.Additionally, the electrical stimulation is administered following anendoscopic procedure. In various embodiments, the electrodes are placedin the stomach.

Also, disclosed herein is a method of preventing inflammation of avisceral organ comprising positioning a stimulatory electrode inproximity of descending efferents in the vagus, innervating the visceralorgan, of an individual in need thereof, and administering repetitivetrains of short pulse electrical stimulation effective in activatingnicotinic receptors. In general, the stimulatory electrodes are placedin the stomach, small intestines, colon or anorectum.

The disclosures described above may further concern positioning one ormore electrodes, such as stimulatory electrodes, relative to the subjectso that the electrode can generate electrical stimulation effective inactivating nicotinic receptors or to block pro-inflammatory spinalreflexes or for electrical stimulation effective for suppressing theinflammatory response in the pancreas or electrical stimulation of thestomach in order to modulate inflammation of the pancreas via 1)activation of anti-inflammatory vagal reflexes involving gastricafferents and pancreatic efferents and/or 2) suppression ofpro-inflammatory axonal reflexes involving the dichotomous branches ofthe spinal nerves and/or 3) activation of other anti-inflammatory neuralpathways between the stomach and pancreas.

Optionally the methods above may additionally include positioning asensor relative to the subject so that the sensor senses the level oftotal electrical stimulation. In certain aspects, the sensor may beoperatively connected to the electrode. Optionally, the method mayinclude periodically detecting the level of electrical stimulation withthe sensor. Still further, the method may include periodicallygenerating non-naturally occurring electrical stimulation with theelectrode.

Certain aspects of the disclosure concern methods of providingelectrical field stimulation to a gastrointestinal organ or thepancreas. Such a method may comprise positioning a first electrode in agastrointestinal organ and/or pancreas and positioning a secondelectrode in the gastrointestinal organ or pancreas. The electrodes maybe stimulatory electrodes. Optionally, the electrodes may be spacedapart from one another. Optionally, the second electrode may be placed1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mm or 20, 30, 40, 50, 60, 70, 80, 90 mmor 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 cm or some range therein from thefirst electrode. In certain cases, the second electrode may bepreferably placed at least about two centimeters from the firstelectrode. Optionally, the method may further comprise electricallystimulating the gastrointestinal organ and/or pancreas simultaneouslythrough the first and the second stimulatory-electrodes, wherein one ofthe first and the second stimulatory electrodes has a positive polarityand wherein the other one of the first and the second stimulatoryelectrodes has a negative polarity, thereby providing electrical fieldstimulation to the gastrointestinal organ and/or pancreas between thefirst and the second stimulatory electrodes.

Certain aspects of the disclosure concern methods of providingelectrical potential gradient in a gastrointestinal organ and/orpancreas. Such a method may comprise positioning a first electrode in agastrointestinal organ and/or pancreas; positioning a second stimulatoryelectrode in the gastrointestinal organ and/or pancreas. The electrodesmay be stimulatory electrodes. Optionally, such a method furthercomprises the second electrode being positioned at a distance from thefirst electrode. Optionally, the second electrode may be placed 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 mm or 20, 30, 40, 50, 60, 70, 80, 90 mm or 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 cm or some range therein from the firstelectrode. In certain cases, the second electrode may be preferablyplaced at least about two centimeters from the first electrode.Optionally the method further comprises electrically stimulating thegastrointestinal organ and/or pancreas simultaneously through the firstand the second stimulatory electrodes. Preferably in such a method,voltage generated by the first electrode differs from voltage generatedby the second electrode. Such a method may result in the providing of anelectrical potential gradient in the gastrointestinal organ and/orpancreas between the first and the second electrodes.

Certain aspects of the disclosure provide methods of treatment bypositioning a plurality of electrodes in a gastrointestinal organ and/orpancreas. Such a method may comprise positioning a first pair of bipolarstimulatory electrodes in contact with a gastrointestinal organ and/orpancreas. Optionally the placement is along the afferent vagus neuralpathway. Optionally, such a method further comprises positioning asecond pair of bipolar stimulatory electrodes in contact with agastrointestinal organ and/or pancreas along the afferent vagus neuralpathway. Optionally, when the use of two pairs of electrodes iscontemplated, such a method further comprises administering a phasedpulse regimentation of the electrical stimulation which progresses fromthe first pair of electrodes to the second pair of electrodes. Such amethod may comprise placement of the electrodes by laproscopic,endoscopic or surgical procedures, through the bore of a needle or somecombination thereof. Such a method may further comprise electricalstimulation in repetitive pulse trains.

Certain aspects of the disclosure provide methods of placing a device inor through a gastrointestinal organ and/or pancreas of a subject. Such amethod may comprise placing the device from the exterior of the subject.Optionally, such a method further comprises inserting at least part of aneedle, such as an end of a needle, from the exterior of a subject intothe gastrointestinal tract of the subject. Optionally, such a methodfurther comprises a needle having an interior bore. In such a method,wherein insertion into a gastrointestinal organ is contemplated thegastrointestinal tract of the subject may be considered to have centerdefined by a wall. The wall of the gastrointestinal tract may beconsidered to have a thickness defining an interior wall adjacent to thecenter and an exterior wall. The method may further comprise inserting aneedle, such as a needle having an interior bore, through the wall ofthe gastrointestinal tract and into the center of the gastrointestinaltract. Optionally or alternatively, wherein placement of a device intothe pancreas of a subject is contemplated, the method may compriseinserting a needle, such as a needle having an interior bore, into thepancreas. The method may further comprise inserting a device through theinterior bore of the needle. Optionally, the method contemplates thatthey device may have engaging means to engage the thickness of the wallof a gastrointestinal organ of the gastrointestinal tract or to engagethe thickness of the pancreas. In methods wherein a needle with aninterior bore and a device with an interior wall engaging means iscontemplated, the method may further comprise inserting the device atleast until the interior wall engaging means extends beyond the interiorbore of the needle. Optionally, such a method further comprises removingthe needle. Optionally, such a method further comprises retracting thedevice until the interior wall engaging means engages the interior wallof the gastrointestinal tract of a gastrointestinal organ of thesubject. Alternatively, such a method further comprises retracting thedevice until the interior wall engaging means engages the thickness of agastrointestinal organ or the thickness of the pancreas.

The methods of placing a device described above may optionally furthercomprise inserting at least part of a needle, such as an end of aneedle, from the exterior of a subject into the gastrointestinal tractof the subject or into the thickness of a gastrointestinal organ of asubject or into the thickness of the pancreas of a subject. Optionally,such a method further comprises a needle having an interior bore. Insuch a method, the gastrointestinal organ may be considered to have athickness. Likewise, in such a method the pancreas may be considered tohave a thickness. In the case of a gastrointestinal organ, thegastrointestinal tract of the subject may be considered to have centerdefined by a wall. The wall of the gastrointestinal tract may beconsidered to have a thickness defining an interior wall adjacent to thecenter and an exterior wall. In either a gastrointestinal organ or apancreas having a thickness, the method may further comprise inserting aneedle, such as a needle having an interior bore, into the thickness ofthe gastrointestinal organ or into the thickness of the pancreas.Optionally, in such a method the needle may be inserted until the end ofthe needle is positioned in the thickness of the wall between theinterior wall and the exterior wall. The method may further compriseinserting a device through the interior bore of the needle. Optionally,in such a method, the device may have an engaging means. Optionally,such a method further comprises inserting the device until the engagingmeans extends beyond the interior bore of the needle into the thicknessof the gastrointestinal organ or the pancreas. Optionally, such a methodfurther comprises removing the needle. Optionally, such a method furthercomprises retracting the device. Optionally, such a method furthercomprises retracting the device until the engaging means engages thethickness. Such a method may thereby place the device in thegastrointestinal wall of the subject or in the pancreas of a subject.Optionally the device may comprise an electrode, such as a stimulatoryelectrode. Optionally the device may comprise a sensor such as anelectrical sensor. Optionally the device may comprise both an electrodeand a sensor. Optionally, the device may comprise a plurality ofelectrodes. Optionally the device may comprise a plurality of sensors.Optionally the device may comprise a plurality of electrodes and onesensor. Optionally the device may comprise a plurality of sensors andone electrode. Optionally the device may comprise a plurality ofelectrodes and sensors.

Certain aspects of the disclosure provide methods of endoscopicplacement or visualization of one or more electrode and/or sensor. Sucha method can comprise using an endoscope for a variety of applicationssuch as but not limited to: 1) visualization and insertion of electrodesand/or sensors with an endoscope 2) endoscopic visualization to guideinsertion of the electrodes and/or sensors, 3) endoscopic insertion ofelectrodes and/or sensors wherein the observation of the placement isdone with a colonoscope or laproscopically and 4) using a plurality ofendoscopes for placement of electrodes or sensors (e.g. one endoscope toobserve placement of an electrode and another endoscope to place theelectrode and/or sensor). Optionally such a method may comprise the useof a single electrode and a single sensor or a plurality of electrodesand sensors or some combination thereof. Optionally, such methodsfurther consist of a subject being sedated prior to or during theendoscopic visualization or placement of the electrode. Optionally, suchmethods further consist of inserting an endoscope or endoscopes in thegastrointestinal tract via the mouth. Optionally, in methods whereinobservation of the placement of one or more electrode and/or sensor iscontemplated, the methods may further comprise the insertion of a needleinto the gastrointestinal tract from the exterior of the subject.Optionally, the methods further comprise a needle penetrating thegastrointestinal tract to the interior of the gastrointestinal tract orto the thickness of the wall of the gastrointestinal tract. In methodswherein a needle is contemplated, the needle may be a hollow needle witha hole in the middle such as a needle having a hollow interior bore. Inother methods, a laproscope or trocar is contemplated to access theexterior of the gastrointestinal tract or the pancreas.

Certain aspects of the disclosure provide methods of colonoscopicplacement or visualization of one or more electrode and/or sensor. Sucha method can comprise using an colonoscope for a variety of applicationssuch as but not limited to: 1) visualization and insertion of electrodesand/or sensors with a colonoscope 2) colonoscopic visualization to guideinsertion of the electrodes and/or sensors, 3) colonoscopic insertion ofelectrodes and/or sensors wherein the observation of the placement isdone with an endoscope or laproscopically and 4) using a plurality ofcolonoscopes for placement of electrodes or sensors (e.g. onecolonoscope to observe placement of an electrode and another colonoscopeto place the electrode and/or sensor). Optionally such a method maycomprise the use of a single electrode and a single sensor or aplurality of electrodes and sensors or some combination thereof.Optionally, such methods further consist of a subject being sedatedprior to or during the colonoscopic visualization or placement of theelectrode. Optionally, such methods further consist of inserting acolonoscope or endoscopes in the gastrointestinal tract via the mouth.Optionally, in methods wherein observation of the placement of one ormore electrode and/or sensor is contemplated, the methods may furthercomprise the insertion of a needle into the gastrointestinal tract fromthe exterior of the subject. Optionally, the methods further comprise aneedle penetrating the gastrointestinal tract to the interior of thegastrointestinal tract or to the thickness of the wall of thegastrointestinal tract. In methods wherein a needle is contemplated, theneedle may be a hollow needle with a hole in the middle such as a needlehaving an hollow interior bore. In other methods, a laproscope or trocaris contemplated to access the exterior of the gastrointestinal tract orthe pancreas.

Certain aspects of the disclosure wherein placement of a deviceendoscopically through the esophagus and into a gastrointestinal organis contemplated, the device may be implanted in the interior wall of thegastrointestinal tract. Optionally, the method comprises preparing anopening in the gastrointestinal tract from the interior wall of thegastrointestinal tract to access the wall of the gastrointestinal tractfor implanting the device. Optionally, the method comprises creating acavity in the wall of the gastrointestinal tract. Optionally, the methodfurther comprises placing the device through the opening into the wallof the gastrointestinal tract. Optionally, the method further comprisesclosing the cavity. According to one variation, after preparing theopening in gastrointestinal tract, a pocket or cavity is prepared in thegastrointestinal tract to receive the device. Optionally, a knife,needle or cutting instrument may be used to prepare an opening in thewall of the gastrointestinal tract. Optionally, such a method furthercomprises injecting a material or solution into the opening forimplanting the device, to form a bleb or blister in the gastrointestinalwall. Optionally, such a method may comprise the use of a tissuedissector to prepare a cavity. Optionally, the tissue dissector may be ablunt dissector, for example, a blunt tool, an expandable compliant ornon-compliant balloon, or another mechanically expanding device, or acutting blade. The dissector may also be a device using an energy sourceto break down or cut tissue such as an electrosurgical cutting orcoagulating device, or an ultrasonic or laser device.

In certain aspects of the disclosure wherein placement of a device iscontemplated, a device may comprise a Teflon™-insulated wire may beextended via the hole of the needle. Optionally the insulated wire maybe peeled off at the distal portion. Optionally, the exposed or peeledoff portion of the inserted Teflon™-insulated wire serves as anelectrode. In methods where insertion of a needle is contemplated, theneedle may be removed after the insertion of the wire. In methods wherea wire is contemplated, the wire may further comprise an engaging means.The engaging means may allow for engagement of the wire with theinterior wall of the gastrointestinal tract or the thickness of the wallof a gastrointestinal organ of the gastrointestinal tract or thepancreas when the wire is pulled from the exterior. Such an engagingmeans may prevent the wire from being further pulled out of the interiorof the gastrointestinal tract or the wall of a gastrointestinal organ ofthe gastrointestinal tract or the pancreas.

Certain aspects of the disclosure contemplate the placement of a device.As will be apparent, the device may comprise an electrode or a sensor ora plurality of electrodes and sensors or a single electrode and aplurality of sensors or a plurality of electrodes and a single sensor.

In certain aspects of the disclosure wherein a device is contemplated,the device may comprise an engaging means wherein the engaging meansitself comprises a plurality of radially extendable arms positioned atan axis perpendicular, acute or obtuse to the insertion axis of thestimulator or sensor. The stimulator or sensor is inserted until theaxis of the plurality of radially extendable arms extends beyond theinterior bore of the needle, at which point the arms radially extend.The electrical stimulator is retracted until the radially extended armsengage the interior wall of the gastrointestinal tract. Optionally, thedevice may have 2, 3, 4, 5, 6, 7, 8, 9 or 10 radially extendable arms ormore. Optionally each radially extendable arm may be positioned to thesame angle. Without being limited to the particular example, eachradially extendable arm may be positioned perpendicular or 90° from theinsertion axis or 120° from the insertion axis or some angle betweenabout 1° and 178° from the insertion axis. Alternatively, each radiallyextendable arm may be positioned to different angles. Without beinglimited to the particular example, one radially extendable arm may bepositioned at an angle of about 1° from the insertion axis, anotherradially extendable arm may be positioned at an angle of about 60° fromthe insertion axis, another radially extendable arm may be positioned atan angle of about 90° from the insertion axis and another radiallyextendable arm may be positioned at an angle of about 136° from theinsertion axis. Optionally, the plurality of radially extendable armsmay be in the same plane. Alternatively, one or more radially extendablearms may be in a different plane as compared to another arm or arms.Without being limited to the particular example, two radially extendablearms may be at the terminal end of the device comprising an insertionaxis wherein the device is positioned with the terminal end towards thecenter of the gastrointestinal tract, while three radially extendablearms may be positioned some distance away, such as 2-20 mm from theterminal end of the device along the insertion axis.

In other aspects of the disclosure wherein a device is contemplated, thedevice may be made of a soft plastic polymer or other medicallyacceptable non irritating material. Optionally, the device may becompressible. Optionally, the device may further comprise a plurality ofelectrodes and/or sensors. Optionally the device may be fixed by sutureto the gastrointestinal tract. Alternatively, the device may be heldstationary with respect to the gastrointestinal tract by a lockingmechanism which surrounds wires leading to the stimulators or sensorsand may be placed on the exterior wall of the gastrointestinal tract oron the skin of a subject. An example of a device that may be fixed orlocked can be found in U.S. Pat. No. 5,292,344.

Certain aspects of the disclosure provide a for a device comprised ofbiocompatible materials that allow it to remain in the environment ofthe gastrointestinal tract or within the gastrointestinal tract wall forthe life of the device, e.g., several weeks, months or years.Optionally, the electrode(s) or sensor(s) may comprise corrosionresistant metals and alloys such as, e.g. platinum, iridium, gold,tantalum, titanium, stainless steel or alloys of one or more of thesemetals, e.g., a platinum/iridium alloy. Other non-conductive parts ofthe device may comprise inert polymers, for example, from the polyolefinfamily, e.g., HDPE (high density polyethylene), PP (polypropylene),UHMWPE (ultra high molecular weight polyethylene), or fluoropolymer suchas PTFE (polytetrafluoroethylene) FEP (fluorinated ethylene propylene)and other members. PMP (polymethylpentene), polysulfone, PMMA(polymethylmethacrylate) may also be used. Softer materials may be used,such as, e.g., silicones, C-Flex, polyurethanes, co-polymer nylons (e.g.PEBAX).

In other aspects of the disclosure wherein a device is contemplated, thedevice may comprise one or more stimulators and/or electrodes.Optionally such a device may further comprise a first and second pair ofattachment members that secure the device in the gastrointestinal tractwall. Optionally, the first attachment members of the device are thefirst to enter the gastrointestinal tract wall. In such a device theattachment members may comprise a flexible material. Optionally theattachment members may be considered tines. Optionally the first tinesmay be considered leading tines that define an obtuse angle with respectto travel of the insertion axis of the device. Optionally, the leadingtines have a diameter of about 1 mm and a length of about 3 mm.Optionally the second tines may define an angle which is obtuse,perpendicular or acute with respect to travel of the insertion axis ofthe device. Optionally, wherein the second tines are at an obtuse anglewith respect to travel of the insertion axis of the device, the secondpair of tines may or may not penetrate the gastrointestinal organ orpancreas. Alternatively, wherein the second tines are at an acute orperpendicular angle with respect to travel of the insertion axis of thedevice, the second pair of tines may not penetrate the gastrointestinaltract wall. Examples of a device of this type may be found in U.S. Pat.No. 6,542,776. Such a device may be inserted into or through agastrointestinal organ or into the pancreas through a trocar from theexterior of the subject. Alternatively, such a device may be insertedfrom the exterior of a subject through a needle with a hollow borewherein the flexible tines are compressed to be at an obtuse angleduring insertion through the needle and into the wall of agastrointestinal organ or pancreas but are uncompressed or lesscompressed when exiting the hollow bore of the needle. Optionally,wherein the second tines are also at any angle relative to the insertiondirection of the insertion axis of the device, they may be compressedinside of the hollow bore of a needle and uncompressed or lesscompressed when exiting the hollow bore of a needle.

In still other aspects of the disclosure wherein a device iscontemplated, the device may be a device comprising stimulators and/orsensors and may be described in detail in U.S. Pat. No. 6,542,776. Sucha device may comprise for example four electrodes which may be placed incontact with the interior or the exterior wall of the gastrointestinaltract or the exterior of the pancreas. Optionally, such a device haselectrodes supported by an electrode attachment member where theelectrodes are in a plane with each other. One may envision fourelectrodes on a flat plate. Such an electrode attachment member may beattached to the gastrointestinal tract wall by sutures or staples.Optionally, the attachment member may have fixed tines at the point ofplacement of the attachment member to the wall of the gastrointestinaltract or the exterior of the pancreas. Such fixed tines may be insertedinto the thickness of a gastrointestinal organ or the thickness of thepancreas in lieu of or in addition to sutures or staples in order toplace the electrode attachment member. Optionally, the electrodeattachment member further comprises an insertion axis extending throughthe electrode attachment member with a plurality of radially spaced armsas described above to place the electrode attachment member. Optionally,the electrode attachment member may be inserted to the body cavity orthrough the hollow bore of a needle. Optionally, the electrodeattachment member may be constructed from a flexible material such as,e.g., silicone elsatomer or similar material. The base materials for theelectrodes which may act as stimulators and/or sensors may be comprisedof platinum, platinum-iridium alloys, titanium and the like. Theelectrodes may optionally be in an uncoated state or may be coated withmaterials such as iridium oxide or titanium nitride or the electrodesmay be platinized or carbonized. Optionally, the electrode attachmentmember has a substantially circular configuration. Alternatively, theelectrode attachment member may be in any suitable configuration such asfor example, square, oval, rectangular, etc. Optionally, the electrodesmay be distributed around the distal surface equidistantly from thecenter of the distal surface.

In certain aspects of the disclosure wherein a device is contemplated,the device may be that which is disclosed in U.S. Pat. No. 7,076,306which is hereby incorporated by reference in its entirety. In certainaspects of the disclosure wherein a device is contemplated, the devicemay be a distributed microsystem setup in which an implanted microsystemis sutured or otherwise attached to the exterior of a gastrointestinalorgan or the exterior of the pancreas. Such a device may be found inU.S. Pat. No. 7,720,539 which is hereby incorporated by reference.Optionally, such a device may incorporate a screw mechanism which mayscrew into the exterior of a gastrointestinal organ or the exterior ofthe pancreas. Such a device may be found in U.S. Pat. No. 7,711,437which is hereby incorporated by reference. In certain aspects of thedisclosure wherein a device is contemplated, the device may include anexpandable member that fixes electrodes in contact with thegastrointestinal tract wall. Optionally such a device is radiallyexpandable. Optionally such a device may be able to expand radially whenpassed through the hollow bore of a needle. Optionally such a device maybe inserted into the thickness of the wall of the gastrointestinaltract. Such a device may be found in U.S. Pat. No. 7,676,270 which ishereby incorporated by reference. Other examples of electricalstimulation devices that may be used according to the present disclosureare found in U.S. Pat. Nos. 7,599,736, 7,477,994, 7,363,084, 7,310,557,7,203,551, 7,177,693 and 7,016,735 which are hereby incorporated byreference. Other examples can be found in U.S. Pat. Pub. Nos.20070049793 and 20050251219 which are hereby incorporated by reference.

In certain aspects of the disclosure wherein a plurality of radiallyextendable arms is contemplated, the arms may be affixed to theinsertion axis of the device. Optionally, arms may be affixed via ahinge mechanism. Optionally, the arms may be affixed via flexibleresilient wires to the insertion axis.

In certain aspects of the disclosure wherein placement of a device iscontemplated, the methods may comprise a gastrointestinal wall tunnelinginstrument. Optionally, such an instrument may further comprise anelongate tubular member having proximal and distal ends and a lumenextending therethrough and an elongate expandable member located at thedistal end of the tubular member. The expandable member may haveproximal and distal ends wherein the proximal end of the expandablemember is connected to the distal end of the tubular member. Theexpandable member may be everted, such that the distal end of theexpandable member is positioned within the lumen of the tubular member.An example of this type of method and instrument can be found inWO/2009/009276 and is herein incorporated by reference.

Certain aspects of the disclosure may pertain to a method of placing adevice and an implantable device as demonstrated in FIG. 6. Referring toFIG. 6A, an electrode lead with an insertion axis 1 is inserted into aneedle 2 with a hollow bore 3. The needle has an entrance tip 4 whichmay be inserted through the skin and into or through the wall of thegastrointestinal tract. The electrode lead 1 may have a first or asingle pair of radially spaced arms 5. Optionally, such arms 5 are in anangular position which is more acute than when passed through the needleas shown in FIG. 6A. Referring to FIG. 6B the radially spaced arms 5 arein an angular position which is less acute than or perpendicular to theelectrode lead with an insertion axis 1 when passed through the needle.Referring to FIG. 6C the lead 1 may have a second or additional pair ofradially spaced arms 6 at a distance from the first pair of radiallyspaced arms 5. Referring to FIG. 6C, each pair of radially spaced arms 5and 6 may be retracted to an angle more acute than when passed throughthe needle 2. Referring to FIG. 6D, the first pair of radially spacedarms 5 and the second or additional pair of radially spaced arms 6 maybe in an angular position which is less acute or perpendicular whenpassed through the hollow bore 3 of the needle 2. Optionally, referringto FIG. 6E the lead 1 may have a second or additional pair of radiallyspaced arms 6 in the same plane from the first pair of radially spacedarms 5. Referring to FIG. 6E, each pair of radially spaced arms 5 and 6may be retracted to an angle more acute than when passed through theneedle 2. Referring to FIG. 6F, the first pair of radially spaced arms 5and the second or additional pair of radially spaced arms 6 may be in anangular position which is less acute or perpendicular when passedthrough the hollow bore 3 of the needle 2. It is also contemplated thata lead 1 may have a plurality of radially spaced arms in an odd numberedconfiguration, such as for example three arms instead of the first orsingle pair of radially spaced arms 5 or the second or additional pairof radially spaced arms as referenced throughout FIG. 6.

Certain aspects of the disclosure concern placement of a device as shownin FIGS. 7A and B. Referring first to FIGS. 6A and 6B, an electrode leadwith an insertion axis 1 and radially spaced arms 5 may be insertedthrough a needle 2 comprising a hollow bore 3 wherein the entrance tipof the needle 4 may be inserted through the skin and into or through thegastrointestinal wall which may alternatively be considered the wall ofthe gastrointestinal tract. Referring to FIG. 7A, the needle 2 with thehollow bore 3 is removed after insertion of the electrode lead with aninsertion axis 1 comprising radially spaced arms 5 such that the leadextends through the skin 8, the panniculus 9 and into thegastrointestinal wall 10. Alternatively, referring to FIG. 7B, the leadextends through the skin 8, the panniculus 9 and through thegastrointestinal wall 10.

Certain aspects of the disclosure pertain to optimal spacing of aplurality of electrodes in the wall of the gastrointestinal tract orthrough the gastrointestinal tract. Referring to FIG. 7C a plurality ofneedles 2 may be connected via a bridge 7 such that a plurality ofelectrode leads with insertion axis 1 comprising radially spaced arms 5are spaced an optimal distance from each other. The bridge may be anylength that achieves optimal spacing. Optionally, the bridge 7 may allowseparation of the needles 2 by a distance of 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 mm or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 cm or some distance therein.Alternatively, referring to FIG. 8A, a needle 2 may first be insertedthrough the skin 9, the panniculus 9 and either into or through thegastrointestinal wall 10. A second needle 17 as shown in FIG. 8B mayinclude a bridge 7 connected to a guide rod 11. Referring to FIG. 8C,the guide rod 11 may be inserted into the needle 2 and an electrode leadwith an insertion axis 1 comprising radially spaced arms 5 may beinserted into the second needle. The guide rod 11 is inserted throughthe first needle 2 as the second needle is inserted through the skin 8,the panniculus 9 and into or through the gastrointestinal wall 10.Referring to FIG. 8C, the second needle 17 may be removed leaving inplace an electrode lead with an insertion axis 1 comprising radiallyspaced arms 5 which may be located in the gastrointestinal tract or inthe gastrointestinal wall 10. Also referring to FIG. 8C, a secondgastrointestinal lead with an insertion axis 1 and a plurality ofradially spaced arms 5 may now be inserted in the first needle where theguide rod was previously located. Referring to FIG. 8D, the first needlemay be removed so that there is more than one electrode lead with aninsertion axis 1 and a plurality of radially spaced arms 5 extendingthrough the skin 8, the panniculus 9 and into or through thegastrointestinal wall 10.

Optionally, in certain aspects of the disclosure where placing of adevice is concerned, the device may be a percutaneous endoscopicgastronomy type device. Referring to FIG. 9A, the device may comprise askin bolster 12 attached or abutting the skin 8 and a gastric bolster 13attached to or abutting the inside of the gastrointestinal wall 10. Aplurality of electric leads 14 may be inserted through the skin bolster12, through the panniculus 9 and through the gastrointestinal tractwall. The electric leads may be insulated and the lead ends 15 exposedand used as electrodes.

In certain aspects of the disclosure wherein an electrode lead with aninsertion axis 1 comprising a plurality of radially spaced arms 5, thelead 1 and the arms 5 may be insulating a conductive wire 16 to serve asan electrode. Referring to FIG. 9B, an electrode lead with an insertionaxis 1 comprising a plurality of radially spaced arms 5 which has beeninserted through a needle 2 may have a conductive wire to serve as anelectrode 16.

Certain aspects of the disclosure concern various means for maintainingthe electrodes in position. Such other may include for example, anchors,sutures, anti-rotation mechanisms and device shape design.

In certain aspects of the disclosure wherein a device is concerned, thedevice may be constructed of a size and shape such that it can bedeployed through the mouth and esophagus with the aid of an endoscope.Optionally, the stimulator is of a generally small profile whendelivered to the implant site. Still further, the implant be constructedand/or implanted so that the device predictably maintains electricalcontact with a muscle layer of the gastrointestinal tract wall.Optionally, the device may be constructed of a configuration or shapethat prevents device rotation, or may be constructed so that devicerotation or movement does not interfere with the electrode/muscle layercontact. Such a device may be found in WO/2002/089655 which is herebyincorporated by reference.

In certain aspects of the disclosure wherein placing a device isconcerned, such methods may include a means for maintaining the devicein proper orientation so that the electrodes, sensors or othertransducers on the device maintain contact with a preferred area orlayer of the gastrointestinal tract wall, for example, so that theelectrodes, sensors or other transducers are preferentially facing adesired wall of the gastrointestinal tract within a submucosal space. Ananti-rotation means may be provided that prevents rotation of theimplant around axes that would move electrodes, sensors or transducersaway from intimate contact with a desired area of the gastrointestinalwall, such as, e.g., a muscle layer or mucosal layer.

In certain aspects of the disclosure wherein placing a device isconcerned, the shape of the device may, for example, have a broad aspectwhen viewing that side of the device intended to be in contact with aparticular layer of the gastrointestinal tract wall (e.g., a musclelayer or mucosal layer); i.e., the top-view of the device has relativelylarge length and width dimensions with respect to the height dimensionof the device given by its side-views. Optionally, the aspect ratio ofthe device, defined as the width of a side-view divided by the height ofthe device is larger than about 1, preferably larger than about 1.4 andmore preferably larger than about 1.8.

In certain aspects of the disclosure wherein placing a device isconcerned, an anti-rotation means may be provided that prevents rotationof the device about an axis parallel to an intended tissue plane ofcontact. A device in one variation is dimensioned so that the aspectratio of the device viewed along an axis parallel to the intended planeof contact is greater than one and preferably greater than 1.4 and morepreferably greater than 1.8.

The aspect ratio as used herein may be the width to height ratio of theaspect viewed along a particular axis. Alternatively, the anti-rotationdevice may comprise an extendible or expandable portion or member thatextends into a position that prevents rotation of the electrodes awayfrom contact with the muscle layer of the gastrointestinal tract wall.

In certain aspects of the disclosure wherein placing a device isconcerned, an anti-rotation means may be provided that prevents rotationof the device about an axis parallel to a common plane on which theelectrodes may lie. Accordingly, a device may be dimensioned so that theaspect ratio of the device viewed along an axis parallel to plane onwhich the electrodes may lie is greater than one and preferably greaterthan 1.4 and more preferably greater than 1.8. The device in thisinstance may be defined by a plane on which the electrodes lie.

In certain aspects of the disclosure wherein placing a device isconcerned, the device may have a relatively small profile when placedthrough the wall or into the wall of the gastrointestinal tract and maybe altered to have a different shape when implanted, to prevent rotationand/or provide optimal sensor/transducer/electrode contact with thegastrointestinal tract wall.

In certain aspects of the disclosure wherein the device is contemplated,the device may be designed to promote encapsulation or tissue ingrowth,e.g. by choice of material, coatings or surface texture. Optionally anelectrode(s) or sensor(s) or surrounding area may be coated with amaterial such as P-15, which is a commercially available compound thatpromotes cellular adhesion and tissue ingrowth.

In certain aspects of the disclosure wherein the device is contemplated,the device or portions of the device may be constructed of or coatedwith substances that inhibit tissue ingrowth.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventors to function well in the practiceof the disclosure, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit or scope of thedisclosure. The following Examples are offered by way of illustrationand not by way of limitation.

Example 1

Based on the hypothesis that irritation of the stomach could affect thepancreas, the neural convergence in the two neighboring organs,specifically focused on dichotomizing branches of afferent neurons, wasexamined. A subset of afferent neurons innervates both the stomach andthe pancreas via dichotomous peripheral branches. This was examined byinjection of two distinct retrogradely transported neuronal dyes intothe pancreas CTB-594 (cholera toxin subunit B [CTB] 594 [“red”];Invitrogen; 24 μl in 12 sites, 2 μl/site at a concentration of 2 μg/ul)and in the stomach (CTB-488 [“green”] at the same concentration usingthe same injection strategy injecting it into the muscle wall and underthe serosa) of rats. Five days later, the animals were euthanized andthe DRGs from thoracic T6-13 segments were harvested and sectioned. Thepercentage of single and double labeled neurons were counted. FIG. 2Ashows the number of double labeled cells expressed as a percentage ofthe total number of gastric- and pancreatic-labeled cells. Of 2333 DRGneurons examined, we found 1779 originating from the stomach, 898originating from the pancreas and 344 from both. Thus, overall about 19%of all pancreatic cells also expressed gastric labeling while 38% allgastric cells also expressed pancreatic labeling. However, these numbersdon't tell the whole story: in T8 for instance more than half of allpancreatic segments also received innervation from the stomach;similarly, in T10 more than 50% of all gastric neurons also innervatedthe pancreas. For the rest of this discussion, we have used the term“gastropancreatic nerve” for nerves that receive input from both thestomach and pancreas. A representative photomicrograph of doublelabeling is shown in FIG. 2B.

As shown in Table 1, most gastropancreatic nerves expressed markers fornociceptive neurons that in equal if not higher frequency than singlelabeled nerves. Nociceptor neurons are considered either peptidergic ornon-peptidergic in origin. CGRP is a commonly used marker for the formerand IB4 for the latter (however, there is considerable overlap as can beseen from the numbers). Both TRPV1 and P2X3 (a purinergic G-proteincoupled receptor) are highly characteristic of nociceptors and are veryimportant molecules in transducing tissue injury into electric signals.An example of an TRPV1 staining in gastropancreatic neuron is shown inFIG. 3.

TABLE 1 Pancreas Stomach Both CGRP 68% 79% 85% IB4 59% 50% 67% P2X3 42%56% 64% TRPV1 73% 78% 71%

Example 2 Activation of Gastropancreatic Neural Reflexes InducePancreatic Injury

Next the functional correlate of this anatomical convergence wasdetermined. It was hypothesized that intragastric capsaicin willactivate TRPV1 on gastric branches of dichotomous gastropancreaticnerves and via an axonal reflex result in edema of the pancreas. Afterpyloric ligaton, intragastric infusion of 1.2 ml of 1.6 μM capsaicin wasfollowed 30 minutes later by harvesting of the pancreas and measurementof water content. The results (FIG. 4) show that intragastric capsaicincauses pancreatic edema, strongly supporting the hypothesis ofgastropancreatic axonal reflexes.

Example 3

Gastric Electrostimulation (GES) was performed in rats injected withcreulein using a pair of electrodes. Creulein is a decapeptide withhypotensive activity that stimulates smooth muscles and increasesdigestive secretions. It is similar to cholecystokinin and the gastrins,but much more potent as a stimulant to gallbladder contraction and alsostimulates release of insulin. A control group of rats had electrodesimplanted but were not stimulated. Electrical stimulation was begun atthe time of injection and continued for 6 hours. Electrical stimulationwas administered in repetitive trains of pulses set on for a range ofperiod between about 0.1 seconds to less than or equal to 5 seconds andset off for a range of period between about 0 to less than or equal to10 minutes. Further, the repetitive trains of pulses were administeredin the range between about IHz. to less than or equal to 150 Hz, a pulsewidth in the range between about 0.1 ms to less than or equal to 2.0 ms,and an amplitude in the range between about 0.1 mA to less than or equalto 20.0 mA. Twenty four hours after the first injection, rats weresacrificed and pancreas harvested. As can be seen from FIG. 5, gastricelectrical stimulation resulted in 50% less edema in the pancreas ascompared to the controls.

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions and the like can bemade without departing from the spirit of the disclosure and these aretherefore considered to be within the scope of the disclosure as definedin the claims which follow. All patents and publications mentionedherein are hereby incorporated by reference as if reproduced in theirentirety.

References

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

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1. A method of preventing acute pancreatitis in a subject comprising:positioning stimulatory electrodes in the stomach of the subject andadministering repetitive pulse trains of gastric electrical stimulationthat are on for 0.1 seconds to 5 seconds and off for up to 10 minutesand are effective for suppressing the inflammatory response in thepancreas.
 2. The method of claim 1, wherein said subject has or isundergoing an endoscopic procedure.
 3. The method of claim 2, whereinsaid endoscopic procedure is selected from the group consisting ofEndoscopic retrograde cholangiopancreatography (ERCP), and endoscopicsphincterotomy.
 4. The method of claim 2, wherein said electricalstimulation is administered concurrently with an endoscopic procedure.5. The method of claim 2, wherein said electrical stimulation isadministered following an endoscopic procedure.
 6. The method of claim1, wherein said repetitive pulse trains are administered in the range ofabout 1 Hz to 150 Hz.
 7. The method of claim 1, wherein said repetitivepulse trains have a pulse width in the range of about 0.1 ms to 2.0 ms.8. The method of claim 1, wherein said repetitive pulse trains have anamplitude in the range of about 0.1 mA to 20.0 mA.
 9. The method ofclaim 1, wherein said electrodes are placed by laproscopic, endoscopicor surgical means.
 10. The method of claim 1, wherein said repetitivetrains of pulses have a pulse width in the range of about 1 ms to 2 ms.11. A method of preventing acute pancreatitis in a subject comprising:positioning a stimulatory electrode in the peritoneal cavity, inproximity of a dichotomously branched spinal nerve innervating thestomach and the pancreas and administering repetitive pulse trains ofelectrical stimulation where the pulses trains are on for 0.1 to 5seconds and off for up to 10 minutes, and are effective for suppressingthe proinflammatory spinal reflexes.
 12. The method of claim 11, whereinsaid repetitive pulse trains are administered in the range of about 1 Hzto 150 Hz.
 13. The method of claim 11, wherein said repetitive pulsetrains have a pulse width in the range of about 0.1 ms to 2.0 ms. 14.The method of claim 11, wherein said repetitive pulse trains have anamplitude in the range of about 0.1 mA to 20.0 mA.
 15. The method ofclaim 11, wherein said electrodes are placed by laproscopic, endoscopicor surgical means.
 16. The method of claim 11, wherein said stimulatoryelectrodes are placed in the stomach, small intestines, colon oranorectum.
 17. The method of claim 11, wherein said repetitive trains ofpulses have a pulse width in the range of about 1 ms to 2 ms.